• Neha Goel, Alexandra E Hernandez, Michael H Antoni, Susan Kesmodel, Paulo S Pinheiro, Erin Kobetz, Nipun Merchant, and Steve Cole.
• Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA.
• Ann. Surg. 2024 Mar 28.

ObjectiveTo determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer (BCa) tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes.Summary Background DataND is associated with shorter BCa recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS.MethodsWe quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology-pro-inflammatory activity (NF-kB, AP-1), sympathetic nervous system (SNS) activity (CREB), and protective cellular responses (IRF, STAT). To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively.ResultsIncreasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB, AP-1, down-regulated IRF, STAT) and SNS activation (up-regulated CREB). Increasing subjective ND (e.g., threat to safety), was associated with up-regulated NF-kB and CREB and down-regulated IRF. These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS.ConclusionsIn the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort.Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

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